Effects of <Emphasis Type="Italic">CYP2C19</Emphasis> and <Emphasis Type="Italic">CYP2C9</Emphasis> genotypes on pharmacokinetic variability of valproic acid in Chinese epileptic patients: nonlinear mixed-effect modeling

Purpose

To evaluate the effects of CYP2C19 and CYP2C9 genotypes on the pharmacokinetic variability of valproic acid (VPA) in epileptic patients using a population pharmacokinetic (PPK) approach.

Methods

VPA concentrations were measured in 287 epileptic patients, who were genotyped for CYP2C19*2/*3 and CYP2C9*3. Patients who were on monotherapy with VPA were divided into two groups, a PPK-model group (n?=?177) and a PPK-valid group (n?=?110). The PPK parameter values for VPA were calculated in the PPK-model group by using the NONMEM software. Ultimately, a biological model and a final model were established. Each model was then used to independently predict the concentrations of the PPK-valid group to validate the two models.

Results

There was a significant effect of the CYP2C19 and CYP2C9 genotypes on the pharmacokinetic (PK) variability (P?<?0.01) in the final PPK model of CL/F. The interindividual CL was calculated according to the final model: CL/F?=?0.0951?×?(1?+?e^{0.0267?×?(3???genotype)})?+?0.0071?×?age (L/h). The coefficient of variation (CV) (omega CL/F) of the final model was 29.3%, while that of the biological model was 31.7%. Based on the genotype, the individual PK parameters can be calculated more accurately than before.

Conclusion

The CYP2C19 and CYP2C9 genotypes significantly influenced the PK variability of VPA, as quantified by NONMEM software.

     

Minimization of CYP2D6 Polymorphic Differences and Improved Bioavailability via Transdermal Administration: Latrepirdine Example

Purpose

Transdermal delivery has the potential to offer improved bioavailability by circumventing first-pass gut and hepatic metabolism. This study evaluated the pharmacokinetics of oral immediate release and transdermal latrepirdine in extensive and poor CYP2D6 metabolizers (EM/PM).

Methods

Latrepirdine transdermal solution was prepared extemporaneously. The solution was applied with occlusive dressing to upper or middle back for 24 h. Each subject received a single dose of 8.14 mg oral, 5 mg transdermal, and 10 mg transdermal (EMs only) latrepirdine free base in a fixed sequence.

Results

Twelve EMs and 7 PMs (50–79 years) enrolled and completed the study. Latrepirdine was well tolerated following both routes of administration. Dose-normalized latrepirdine total exposures were approximately 11-fold and 1.5-fold higher in EMs and PMs, respectively following administration of transdermal relative to oral. Differences between EM and PM latrepirdine exposures were decreased, with PMs having 1.9- and 2.7-fold higher peak and total exposures, respectively, following transdermal administration compared to 11- and 20-fold higher exposures, respectively, following oral administration.

Conclusion

Transdermal delivery can potentially mitigate the large intersubject differences observed with compounds metabolized primarily by CYP2D6. Transdermal delivery was readily accomplished in the clinic using an extemporaneously prepared solution [NCT00990613].

     

Influence of clinical and genetic factors on warfarin dose requirements among Japanese patients

Objective

The aim of this study was to investigate the influence of clinical and genetic factors on warfarin dose requirements in the Japanese population.

Methods

We enrolled 125 patients on stable warfarin anticoagulant therapy with an international normalized ratio maintained between 1.5 and 3.0. PCR-based methods were performed to analyze genetic polymorphisms in the genes pharmacokinetically and pharmacodynamically related to warfarin reactions, including cytochrome P450 (CYP) 2C9, vitamin K epoxide reductase complex subunit 1 (VKORC1), gamma-glutamyl carboxylase (GGCX) and factor VII (FVII).

Results

The presence of CYP2C9*3 and VKORC1-1639G>A had a significant impact on the mean maintenance dose of warfarin (CYP2C9*1/*1 2.74?±?1.24 mg/day vs. *1/*3 and *3/*3 1.56?±?0.85 mg/day, P?=?0.009; VKORC1-1639AA 2.42?±?0.95 mg/day vs. GA 3.71?±?1.43 mg/day vs. GG 7.25?±?0.35 mg/day, P?<?0.001). In the multiple linear regression model, the combination of age, body surface area, and genotypes of CYP2C9*3 and VKORC1-1639G>A explained 54.8% of the variance in warfarin dose requirements.

Conclusions

The influences of CYP2C9*3 and VKORC1-1639G>A on the maintenance dose of warfarin were well-defined in Japanese patients, while polymorphisms of GGCX and FVII did not affect it. The model established in this study might provide us most likely individual maintenance dose based on clinical and genetic backgrounds.

     

Evaluation of lansoprazole as a probe for assessing cytochrome P450 2C19 activity and genotype–phenotype correlation in childhood

Purpose

Lansoprazole, a cytochrome P450 2C19 (CYP2C19) substrate, has been widely used in children to manage acid-related diseases. CYP2C19 exhibits marked genetic polymorphisms, and distribution of these polymorphisms varies among different ethnic groups. There is limited data regarding the use of probe drugs for determining CYP2C19 activity in children. The aim of this study was to evaluate lansoprazole as an in vivo phenotyping probe for assessing CYP2C19 activity in children.

Methods

The CYP2C19*2, *3, and *17 variants were determined in 244 children. Three hours after a single oral dose of lansoprazole (n?=?94) or omeprazole (n?=?19), plasma lansoprazole and 5-hydroxy lansoprazole or omeprazole and 5-hydroxy omeprazole concentrations were analyzed by high-performance liquid chromatography.

Results

The CYP2C19*17 was the most frequent variant allele (24.4%). The group of patients with CYP2C19*17*17 genotype had a 70% lower (p?CYP2C19*1*1 genotype group, whereas the CYP2C19*2*2 group had 6.9-fold higher (p?*17*17 [mean ± standard deviation (SD); 2.8?±?2.1] group and higher in the *2*2 group (63.5?±?12.2) compared with that of the *1*1 genotype group (6.1?±?4.5).

Conclusion

According to our results from a Turkish pediatric population, lansoprazole is a suitable probe drug for phenotyping CYP2C19. The CYP2C19*2 and *17 variants should be taken into consideration in predicting the clinical outcome of therapy with lansoprazole in the pediatric population.

     

Effects of terbinafine and itraconazole on the pharmacokinetics of orally administered tramadol

Background

Tramadol is widely used for acute, chronic, and neuropathic pain. Its primary active metabolite is O-desmethyltramadol (M1), which is mainly accountable for the μ-opioid receptor-related analgesic effect. Tramadol is metabolized to M1 mainly by cytochrome P450 (CYP)2D6 enzyme and to other metabolites by CYP3A4 and CYP2B6. We investigated the possible interaction of tramadol with the antifungal agents terbinafine (CYP2D6 inhibitor) and itraconazole (CYP3A4 inhibitor).

Methods

We used a randomized placebo-controlled crossover study design with 12 healthy subjects, of which 8 were extensive and 4 were ultrarapid CYP2D6 metabolizers. On the pretreatment day 4 with terbinafine (250 mg once daily), itraconazole (200 mg once daily) or placebo, subjects were given tramadol 50 mg orally. Plasma concentrations of tramadol and M1 were determined over 48 h and some pharmacodynamic effects over 12 h. Pharmacokinetic variables were calculated using standard non-compartmental methods.

Results

Terbinafine increased the area under plasma concentration–time curve (AUC_0-∞) of tramadol by 115 % and decreased the AUC_0-∞ of M1 by 64 % (P?<?0.001). Terbinafine increased the peak concentration (C _max) of tramadol by 53 % (P?<?0.001) and decreased the C _max of M1 by 79 % (P?<?0.001). After terbinafine pretreatment the elimination half-life of tramadol and M1 were increased by 48 and 50 %, respectively (P?<?0.001). Terbinafine reduced subjective drug effect of tramadol (P?<?0.001). Itraconazole had minor effects on tramadol pharmacokinetics.

Conclusions

Terbinafine may reduce the opioid effect of tramadol and increase the risk of its monoaminergic adverse effects. Itraconazole has no meaningful interaction with tramadol in subjects who have functional CYP2D6 enzyme.

     

<Emphasis Type="BoldItalic">CYP2D6</Emphasis> Genetic Variation and Beta-Blocker Maintenance Dose in Patients with Heart Failure

Purpose

This study examined whether a CYP2D6 polymorphism (CYP2D6*4) was related to beta-blocker maintenance dose in patients with heart failure.

Methods

Logistic regression modeling was utilized in a retrospective chart-review analysis of heart-failure patients (60% Male, 90% of European descent) to assess whether CYP2D6*4 (non-functional CYP2D6 allele present in 1 of 5 individuals of European descent) is associated with maintenance dose of carvedilol (n?=?65) or metoprolol (n?=?33).

Results

CYP2D6*4 was associated with lower maintenance dose of metoprolol (OR 0.13 [95% CI 0.02–0.75] p?=?0.023), and a trend was observed between CYP2D6*4 and higher maintenance dose of carvedilol (OR 2.94 [95% CI 0.84–10.30] p?=?0.093). None of the patients that carried CYP2D6*4 achieved the recommended target dose of metoprolol (200 mg/day).

Conclusion

Consistent with the role of CYP2D6 in the metabolism of metoprolol, the tolerated maintenance dose of metoprolol was lower in CYP2D6*4 carriers compared to non-carriers. Consistent with the role of CYP2D6 in activation of carvedilol, tolerated maintenance dose of carvedilol was higher in CYP2D6*4 carriers compared to non-carriers. Further investigation is warranted to ascertain the potential of CYP2D6 as a potential predictive biomarker of beta-blocker maintenance dose in heart failure patients.

     

Evaluation of Time Dependent Inhibition Assays for Marketed Oncology Drugs: Comparison of Human Hepatocytes and Liver Microsomes in the Presence and Absence of Human Plasma

Purpose

To evaluate an alternative in vitro system which can provide more quantitatively accurate drug drug interaction (DDI) prediction for 10 protein kinase inhibitors for which DDI risk was over-predicted by inhibition data generated in human liver microsomes (HLM).

Methods

Three cryopreserved human hepatocyte (hHEP) systems: 1) plated hHEPs; 2) hHEPs suspended in Dulbecco’s Modified Eagle Medium (DMEM) and 3) hHEPs suspended in human plasma (plasma hHEPs) were developed to detect CYP3A time dependent inhibition, and the static mechanistic model was used to predict clinical outcomes.

Results

A general trend was observed in the CYP3A inactivation potency (k _inact /K _{I, app} ) as HLM > plated > DMEM ≥ plasma hHEPs. Using the static mechanistic model, DDIs predicted using parameters estimated from plated, DMEM and plasma hHEPs had 84, 74 and 95% accuracy (out of 19 clinical interaction studies) within 2-fold of the reported interaction, respectively. They demonstrated significant improvement compared to the DDIs predicted using parameters estimated from HLMs where 58% accuracy was obtained.

Conclusions

Based on 19 DDIs, plasma hHEPs demonstrate a more reliable clinical DDI prediction for 10 protein kinase inhibitors and prototypical CYP3A time dependent inhibitors.

     

Effect of the CYP2C19 genotype on the pharmacokinetics of icotinib in healthy male volunteers

Purpose

Icotinib hydrochloride {4-[(3-ethynylphenyl)amino]-6,7-benzo-12-crown-4-quinazoline hydrochloride}, a novel epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), was designed for the treatment of non-small cell lung cancer (NSCLC). In the present study, we investigated the influence of the CYP2C19*2 and CYP2C19*3 alleles on the pharmacokinetics of icotinib in healthy Chinese volunteers.

Methods

In a single-dose pharmacokinetic study, 12 healthy Chinese volunteers received an oral dose of 600?mg of icotinib. Plasma was sampled for up to 72?h post-dose, followed by quantification of icotinib by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS-MS).

Results

Five subjects genotyped as homozygous extensive metabolizers (CYP2C19*1/*1), 6 subjects genotyped as heterozygous extensive metabolizers (CYP2C19*1/*2 or CYP2C19*1/*3), and 1 subject genotyped as a poor metabolizer (CYP2C19*2/*3) and was withdrawn from the research because of urticaria. The mean icotinib AUC_0-∞ and C_max (14.56 ±5.31?h?mg/L and 2.32?±?0.49?μg/mL) in homozygous EMs was 1.56 and 1.41-fold lower than that in heterozygous EMs (22.7?±?6.11 and 3.28?±?0.48, P?=?0.046 and 0.047). The mean CL/F (44.18?±?12.17?L/h) in homozygous EMs was 1.55-fold higher than that in heterozygous EMs (28.42?±?9.23?L/h, P?=?0.013).

Conclusions

The data showed that the pharmacokinetics of icotinib differ significantly between homozygous EMs and heterozygous EMs in CYP2C19.     

Effects of genetic polymorphisms of <Emphasis Type="Italic">CYP2C19</Emphasis> on the pharmacokinetics of zolpidem

Zolpidem is indicated for the short-term treatment of insomnia and it is predominantly metabolized by CYP3A4, and to a lesser extent by CYP2C19, CYP1A2, and CYP2C9. Therefore, we evaluated the effects of CYP2C19 genetic polymorphisms on the pharmacokinetics of zolpidem in healthy male subjects. Thirty-two male subjects were recruited and all subjects were classified into three groups according to their genotypes: CYP2C19EM (CYP2C19*1/*1, n?=?12), CYP2C19IM (CYP2C19*1/*2 or *1/*3, n?=?10), and CYP2C19PM (CYP2C19*2/*2, *2/*3 or *3/*3, n?=?10). The pharmacokinetic parameters of zolpidem were compared in three CYP2C19 genotype groups after zolpidem administration with or without a CYP3A4 inhibitor at steady-state concentration. Plasma concentrations of zolpidem were determined up to 12 h after drug administration by liquid chromatography-tandem mass spectrometry method. The maximum plasma concentration (C_max) differed, but mean total area under the plasma concentration–time curve (AUC_inf), half-life (t_1/2), and apparent oral clearance (CL/F) of zolpidem administered alone did not significantly differ among the three different CYP2C19 genotype groups. Furthermore, when zolpidem was administered with a CYP3A4 inhibitor at steady-state concentration, there were no significant differences in any of the pharmacokinetic parameters of zolpidem in relation to CYP2C19 genotypes. In conclusion, we did not find any evidence for the impact of CYP2C19 genetic polymorphisms on the pharmacokinetic parameters of zolpidem.     

Pharmacokinetic– pharmacodynamic analysis of the role of CYP2C19 genotypes in short-term rabeprazole-based triple therapy against Helicobacter pylori

AIMS

The aim was to explore the role of CYP2C19 polymorphism in short-term rabeprazole-based triple therapy against Helicobacter pylori infection.

METHODS

Patients with H. pylori infection were tested for CYP2C19 genotype as poor metabolizers (PMs) or extensive metabolizers (EMs, homozygous EM or heterozygous EM) and given rabeprazole for 7 days. Antibiotics (clarithromycin and amoxicillin) were given on days 1–4, days 4–7, or days 1–7. A direct link model with an effect compartment was used in the population pharmacokinetic–pharmacodynamic analysis. The status of H. pylori infection was evaluated.

RESULTS

Rabeprazole clearance was lower in CYP2C19 PMs than in EMs (with average values of 10.7 vs. 16.8 l h⁻¹ in PMs and EMs, respectively), resulting in higher plasma levels in the former group. The values of EC₅₀ and k_eo of gastrin response increased with multiple doses of rabeprazole. The k_eo values were lower in CYP2C19 PMs than in EMs on day 1 (0.012 vs. 0.017 × 10⁻⁴ l min⁻¹), and higher than in EMs on day 4 (0.804 vs. 0.169 × 10⁻⁴ l min⁻¹) of rabeprazole treatment. The predicted gastrin-time profile showed a higher response in CYP2C19 PMs than in EMs on days 4 and 7. Helicobacter pylori was eradicated in all CYP2C19 PMs except in one patient infected by a resistant strain. In contrast, in CYP2C19 EMs the eradication rates ranged from 58 to 85%.

CONCLUSIONS

CYP2C19 genotypes play a role in H. pylori eradication therapy. Rabeprazole-based short-term triple therapy may be applicable in CYP2C19 PMs for H. pylori eradication.     

Daytime <Emphasis Type="Italic">Ayahuasca</Emphasis> administration modulates REM and slow-wave sleep in healthy volunteers

Objectives

Ayahuasca is a traditional South American psychoactive beverage and the central sacrament of Brazilian-based religious groups, with followers in Europe and the United States. The tea contains the psychedelic indole N,N-dimethyltryptamine (DMT) and β-carboline alkaloids with monoamine oxidase-inhibiting properties that render DMT orally active. DMT interacts with serotonergic neurotransmission acting as a partial agonist at 5-HT_1A and 5-HT_2A/2C receptor sites. Given the role played by serotonin in the regulation of the sleep/wake cycle, we investigated the effects of daytime ayahuasca consumption in sleep parameters.

Measurements and results

Subjective sleep quality, polysomnography (PSG), and spectral analysis were assessed in a group of 22 healthy male volunteers after the administration of a placebo, an ayahuasca dose equivalent to 1 mg DMT kg^?1 body weight, and 20 mg d-amphetamine, a proaminergic drug, as a positive control. Results show that ayahuasca did not induce any subjectively perceived deterioration of sleep quality or PSG-measured disruptions of sleep initiation or maintenance, in contrast with d-amphetamine, which delayed sleep initiation, disrupted sleep maintenance, induced a predominance of ‘light’ vs ‘deep’ sleep and significantly impaired subjective sleep quality. PSG analysis also showed that similarly to d-amphetamine, ayahuasca inhibits rapid eye movement (REM) sleep, decreasing its duration, both in absolute values and as a percentage of total sleep time, and shows a trend increase in its onset latency. Spectral analysis showed that d-amphetamine and ayahuasca increased power in the high frequency range, mainly during stage 2. Remarkably, whereas slow-wave sleep (SWS) power in the first night cycle, an indicator of sleep pressure, was decreased by d-amphetamine, ayahuasca enhanced power in this frequency band.

Conclusions

Results show that daytime serotonergic psychedelic drug administration leads to measurable changes in PSG and sleep power spectrum and suggest an interaction between these drugs and brain circuits modulating REM and SWS.

     

Testing the validity of<Emphasis Type="Italic"> c-fos</Emphasis> expression profiling to aid the therapeutic classification of psychoactive drugs

Rationale

Different stimuli, including pharmacological stimuli, induce different neuroanatomical profiles of c-fos expression. Can these profiles be used in classifying psychoactive drugs and predicting therapeutic utility?

Objective

To test the validity of c-fos expression profiling to aid therapeutic classification.

Methods

Anxiolytics, antidepressants, antipsychotics and psychostimulants were compared. (i) A meta-analysis was performed and profiles compiled from literature reports of changes in c-fos expression in rat brain regions, measured by in situ hybridisation histochemistry or immunohistochemistry, after acute injection of psychoactive drugs. (ii) Male rat brains were profiled for changes in c-fos mRNA expression induced by acute injection of psychoactive drugs.

Results

(i) The meta-analysis showed that anxiolytics activate few (mostly stress-related) brain regions; antidepressants activate more regions, including the central amygdaloid nucleus; antipsychotics activate more regions still, including the nucleus accumbens and striatal areas; and psychostimulants activate the greatest number of all, including the most cortical regions (especially the piriform cortex). Profiles also varied within drug classes. (ii) Our experimental profiles confirmed and extended meta-analysis profiles, showing more downregulation. (iii) Sites activated by mirtazapine (an antidepressant not previously profiled) matched those of the antidepressant imipramine.

Conclusions

(i) Differences between drug classes support their classification by means of c-fos profiling. Differences within classes may reflect mechanistic variations. (ii) Greater downregulation in our experiments might be because of inclusion of low, clinically relevant, drug doses and fuller coverage of brain regions. (iii) The agreement between mirtazapine and imipramine increases our confidence in the validity of c-fos expression profiling to aid drug classification and predict therapeutic utility.

     

Strategy for CYP3A Induction Risk Assessment from Preclinical Signal to Human: a Case Example of a Late-Stage Discovery Compound

Purpose

The exposure of G2917 decreased by four-fold at oral doses of 100 mg/kg twice daily for seven days in cynomolgus monkeys. Additional investigative work was conducted to understand: (1) the causes for the significant reduction in G2917 exposure in monkeys; (2) the extrapolation of in vitro induction data to in vivo findings in monkeys, and (3) the relevance of this pre-clinical finding to humans at the projected human efficacious dose.

Methods

Pharmacokinetic and induction potency (in vitro and in vivo) of G2917 in monkeys, and the in vitro human induction potency were studied. The hepatic CYP3A biomarkers 4β-hydroxycholesterol (4β-HC) and 6β-hydroxycortisol/cortisol ratio (6β-OHC/C) were monitored in in vivo studies. The static mechanistic model was used to quantitatively understand the in vitro-in vivo extrapolation (IVIVE) on the magnitude of induction retrospectively. Physiologically based pharmacokinetic (PBPK) modeling was used to predict the human pharmacokinetics and induction-based drug-drug interactions (DDI).

Results

All in vitro and in vivo data indicate that the significant reduction in exposure of G2917 in monkeys is caused by auto-induction of CYP3A. The mechanistic understanding of IVIVE of G2917 induction in monkey provides higher confidence in the induction risk prediction in human using the PBPK modeling. PBPK model analysis predicted minimum auto-induction and DDI liability in humans at the predicted efficacious dose.

Conclusions

The learning of this example provided a strategy to address the human CYP3A induction risk prospectively when there is an auto-induction finding in preclinical toxicology study.

     

Inflation of Type I Error in the Evaluation of Scaled Average Bioequivalence,and a Method for its Control

Purpose

To verify previously reported findings for the European Medicines Agency’s method for Average Bioequivalence with Expanding Limits (ABEL) for assessing highly variable drugs and to extend the assessment for other replicate designs in a wide range of sample sizes and CVs. To explore the properties of a new modified method which maintains the consumer risk ≤0.05 in all cases.

Methods

Monte-Carlo simulations of three different replicate designs covering a wide range of sample sizes and intra-subject variabilities were performed.

Results

At the switching variability of CV _wR 30% the consumer risk is substantially inflated to up to 9.2%, which translates into a relative increase of up to 84%. The critical region of inflated type I errors ranges approximately from CV _wR 25 up to 45%. The proposed method of iteratively adjusting α maintains the consumer risk at the desired level of ≤5% independent from design, variability, and sample size.

Conclusions

Applying the European Medicines Agency’s ABEL method at the nominal level of 0.05 inflates the type I error to an unacceptable degree, especially close to a CV _wR of 30%. To control the type I error nominal levels ≤0.05 should be employed. Iteratively adjusting α is suggested to find optimal levels of the test.

     

Pharmacokinetic/Pharmacodynamic Relationship of Gabapentin in a CFA-induced Inflammatory Hyperalgesia Rat Model

Purpose

Gabapentin displays non-linear drug disposition, which complicates dosing for optimal therapeutic effect. Thus, the current study was performed to elucidate the pharmacokinetic/pharmacodynamic (PKPD) relationship of gabapentin’s effect on mechanical hypersensitivity in a rat model of CFA-induced inflammatory hyperalgesia.

Methods

A semi-mechanistic population-based PKPD model was developed using nonlinear mixed-effects modelling, based on gabapentin plasma and brain extracellular fluid (ECF) time-concentration data and measurements of CFA-evoked mechanical hyperalgesia following administration of a range of gabapentin doses (oral and intravenous).

Results

The plasma/brain ECF concentration-time profiles of gabapentin were adequately described with a two-compartment plasma model with saturable intestinal absorption rate (K _m ?=?44.1 mg/kg, V _max ?=?41.9 mg/h?kg) and dose-dependent oral bioavailability linked to brain ECF concentration through a transit compartment. Brain ECF concentration was directly linked to a sigmoid E _max function describing reversal of hyperalgesia (EC _{50, plasma} ?=?16.7 μg/mL, EC _{50, brain} ?=?3.3 μg/mL).

Conclusions

The proposed semi-mechanistic population-based PKPD model provides further knowledge into the understanding of gabapentin’s non-linear pharmacokinetics and the link between plasma/brain disposition and anti-hyperalgesic effects. The model suggests that intestinal absorption is the primary source of non-linearity and that the investigated rat model provides reasonable predictions of clinically effective plasma concentrations for gabapentin.

     

Fractal Aspects of Static and Dynamic Flow Properties of Pharmaceutical Excipients

Purpose

Characterisation of powder flow is important for pharmaceutical processing and manufacturing. This work aims at a better understanding of how fractal particle and bulk properties affect the static and dynamic flow of excipients.

Methods

Traditional methods of flowability testing, e.g. the angle of repose or the flow through an orifice, were complemented by avalanching in a rotational drum. Dynamic image analysis provided a fractal contour line dimension of the powder bulk in the drum (bD _F ). This was compared to the contour line fractal dimension of particles (pD _F ) as obtained from the box-counting method. Avalanche testing was able to measure also cohesive materials that were otherwise difficult or not measurable at all using the classical methods.

Results

The values of the avalanche energy were in good agreement with the different flow properties of the samples. These flow properties showed good correlations with bD _F in that poor flow properties were associated with a more rugged contour line of the bulk and hence higher bD _F .

Conclusions

Interestingly, there was no correlation observed between pD _F and bD _F , which may suggest that a distinct bulk structure typically emerges from the particles under dynamic flow. Future research should further clarify how fractal powder aspects affect pharmaceutical manufacturing processes.

     

Development and performance of npde for the evaluation of time-to-event models

Purpose

Normalised prediction distribution errors (npde) are used to graphically and statistically evaluate mixed-effect models for continuous responses. In this study, our aim was to extend npde to time-to-event (TTE) models and evaluate their performance.

Methods

Let V denote a dataset with censored TTE observations. The null hypothesis (H₀) is that observations in V can be described by model M. We extended npde to TTE models using imputations to take into account censoring. We then evaluated their performance in terms of type I error and power to detect model misspecifications for TTE data by means of a simulation study with different sample sizes.

Results

Type I error was found to be close to the expected 5% significance level for all sample sizes tested. The npde were able to detect misspecifications in the baseline hazard as well as in the link between the longitudinal variable and the survival function. The ability to detect model misspecifications increased as the difference in the shape of the survival function became more apparent. As expected, the power also increased as the sample size increased. Imputing the censored events tended to decrease the percentage of rejections.

Conclusions

We have shown that npde can be readily extended to TTE data and that they perform well with an adequate type I error.

     

Simulation-Based Evaluation of PK/PD Indices for Meropenem Across Patient Groups and Experimental Designs

Purpose

Antibiotic dose predictions based on PK/PD indices rely on that the index type and magnitude is insensitive to the pharmacokinetics (PK), the dosing regimen, and bacterial susceptibility. In this work we perform simulations to challenge these assumptions for meropenem and Pseudomonas aeruginosa.

Methods

A published murine dose fractionation study was replicated in silico. The sensitivity of the PK/PD index towards experimental design, drug susceptibility, uncertainty in MIC and different PK profiles was evaluated.

Results

The previous murine study data were well replicated with fT?>?MIC selected as the best predictor. However, for increased dosing frequencies fAUC/MIC was found to be more predictive and the magnitude of the index was sensitive to drug susceptibility. With human PK fT?>?MIC and fAUC/MIC had similar predictive capacities with preference for fT?>?MIC when short t_1/2 and fAUC/MIC when long t_1/2.

Conclusions

A longitudinal PKPD model based on in vitro data successfully predicted a previous in vivo study of meropenem. The type and magnitude of the PK/PD index were sensitive to the experimental design, the MIC and the PK. Therefore, it may be preferable to perform simulations for dose selection based on an integrated PK-PKPD model rather than using a fixed PK/PD index target.

     

Comparing Mechanistic and Preclinical Predictions of Volume of Distribution on a Large Set of Drugs

Purpose

Volume of distribution at steady state (Vd_ss) is a fundamental pharmacokinetic (PK) parameter driven predominantly by passive processes and physicochemical properties of the compound. Human Vd_ss can be estimated using in silico mechanistic methods or empirically scaled from Vd_ss values obtained from preclinical species. In this study the accuracy and the complementarity of these two approaches are analyzed leveraging a large data set (over 150 marketed drugs).

Methods

For all the drugs analyzed in this study experimental in vitro measurements of LogP, plasma protein binding and pKa are used as input for the mechanistic in silico model to predict human Vd_ss. The software used for predicting human tissue partition coefficients and Vd_ss based on the method described by Rodgers and Rowland is made available as supporting information.

Results

This assessment indicates that overall the in silico mechanistic model presented by Rodgers and Rowland is comparably accurate or superior to empirical approaches based on the extrapolation of in vivo data from preclinical species.

Conclusions

These results illustrate the great potential of mechanistic in silico models to accurately predict Vd_ss in humans. This in silico method does not rely on in vivo data and is, consequently, significantly time and resource sparing. The success of this in silico model further suggests that reasonable predictability of Vd_ss in preclinical species could be obtained by a similar process.